Mclaughlin Research Institute For Biomedical Sciences

CENTER FOR INTEGRATED BIOMEDICAL AND RURAL HEALTH RESEARCH - OVERALL PLAN: SUMMARY THE OVERALL GOAL OF THIS CENTER OF BIOMEDICAL RESEARCH EXCELLENCE (COBRE) APPLICATION IS TO STRENGTHEN THE BIOMEDICAL RESEARCH INFRASTRUCTURE IN MONTANA WITH A FOCUS ON THE CENTRAL, MULTI-DISCIPLINARY THEME OF INTEGRATED BIOMEDICAL AND RURAL HEALTH RESEARCH, A SUBJECT THAT IS BOTH SUFFICIENTLY BROAD TO ENABLE RECRUITMENT OF DIVERSE FACULTY AND SUFFICIENTLY FOCUSED TO BUILD COHESIVENESS AROUND A COMMON GOAL TO ADDRESS RURAL HEALTH IN A MULTI- DISCIPLINARY FASHION THAT INCLUDES BASIC, TRANSLATIONAL AND CLINICAL STUDIES. THE CENTER FOR BIOMEDICAL AND RURAL HEALTH RESEARCH ENCOMPASSES MENTORSHIP AND COLLABORATION BETWEEN FACULTY IN THE ESTABLISHED PARTNERSHIP BETWEEN THE MCLAUGHLIN RESEARCH INSTITUTE, THE TOURO UNIVERSITY COLLEGE OF OSTEOPATHIC MEDICINE - MONTANA, AND THE BENEFIS HEALTHCARE SYSTEM, THE LARGEST COMPREHENSIVE PROVIDER IN CENTRAL MONTANA EXTENDING ACROSS 38,000 SQUARE MILES WITH OUTREACH SERVICES PRESENT IN 94 PERCENT OF MONTANA’S COUNTIES. WE FOCUS ON BUILDING CAPACITY IN RESEARCH ON HEALTH PROBLEMS THAT ARE ESPECIALLY OF CONCERN AND/OR PREVALENCE IN RURAL ENVIRONMENTS WITH THREE SPECIFIC AIMS TO: 1) ENHANCE THE SUCCESS OF RESEARCH PROJECT LEADERS (RPLS) ALONG THE INTEGRATED TRAJECTORY FROM BENCH TO TRANSLATIONAL ANIMAL MODELS, TO CLINICAL APPLICATIONS. 2) RECRUIT A MINIMUM OF EIGHT ADDITIONAL FACULTY, IN PHASE I, AS RPLS AND PILOT PROJECT INVESTIGATORS (PPIS) TO INCREASE THE NUMBER OF INVESTIGATORS, AND THEIR SCOPE AND IMPACT, IN INTEGRATED BIOMEDICAL RESEARCH. 3) BUILD AND MAINTAIN TWO CRITICAL CORE FACILITIES THAT SUPPORT EXPANSION OF RESEARCH INFRASTRUCTURE. TO ACCOMPLISH OUR AIMS, WE PRESENT FOUR INITIAL PROJECTS FOCUSED ON NEUROLOGICAL DISEASES, DISEASES THAT ARE COMMON AND DISTINCTIVELY DEVASTATING, IN RURAL ENVIRONMENTS: NEUTROPHIL APOPTOSIS IN ALZHEIMER’S DISEASE PATHOGENESIS, AGE-RELATED MACULAR DEGENERATION AND EXOSOME RELEASE, MISFOLDED SOD-1 AND Α-SYNUCLEIN PROTEINS IN IDIOPATHIC PARKINSON’S DISEASE (PD), AND COMPREHENSIVE PHENOTYPIC PROFILING OF CHRONIC WASTING DISEASE (CWD). EACH PROJECT IS LED BY A NEW OR AN EARLY- STAGE INVESTIGATOR WITH AN ENGAGED MENTORING TEAM SPECIFICALLY TAILORED TO THEIR CAREER DEVELOPMENT. SUPPORTING THESE PROJECTS ARE TWO CORES: THE ADMINISTRATIVE CORE AND THE GENE EDITING AND MOUSE MODELS ASSESSMENT (GEMMA) CORE. THIS APPLICATION IS SIGNIFICANT AS IT ESTABLISHES A UNIQUE AND SUSTAINABLE CENTER THAT SERVES THE TWO PRIMARY PURPOSES OF SUPPORTING CAREER DEVELOPMENT OF NEW AND EARLY-STAGE INVESTIGATORS IN A UNIQUE GEOGRAPHICAL AND SOCIO-CULTURAL AREA OF MONTANA AND OF ADVANCING OUR UNDERSTANDING OF CONDITIONS OF SPECIAL CONCERN AND/OR PREVALENCE IN RURAL COMMUNITIES. THE APPLICATION IS INNOVATIVE IN MULTIPLE ASPECTS BUT ESPECIALLY AS IT: 1) TAPS INTO THE STRENGTHS AND RESOURCES OF AN EXTENSIVE AND UNDER-UTILIZED SECTOR OF THE HEALTHCARE COMMUNITY THROUGH A PARTNERSHIP BETWEEN AN INDEPENDENT NONPROFIT RESEARCH ORGANIZATION, AN OSTEOPATHIC MEDICAL CAMPUS AND A RURAL-SERVING HEALTHCARE SYSTEM, AND 2) SERVES THE DUAL PURPOSE OF PROVIDING UNPRECEDENTED OPPORTUNITIES FOR EXPANSION OF BIOMEDICAL RESEARCH, TALENT RECRUITMENT AND INNOVATION IN A RURAL REGION OF THE UNITED STATES WHILE ALSO PROVIDING THE PHYSICAL AND INTELLECTUAL PRESENCE IN SITU THAT IS REQUIRED TO INCREASE PUBLIC TRUST IN BIOMEDICAL RESEARCH IN THE NORTHERN ROCKY MOUNTAIN FRONT AND ADJACENT COMMUNITIES.

GENETICS OF PRION SUSCEPTIBILITY IN VITRO

HOMEOSTATIC CONTROL OF THE NMDA RECEPTOR CO-AGONIST D-SERINE BY SLC1A4

MUTANT HUMAN A-SYNUCLEIN TOXICITY IN MICE

DISSECTION OF THE TRANSCRIPTIONAL NETWORK OF HUMAN PRIMORDIAL GERM CELLS

GENETIC CONTROL OF SCHWANN CELL DIFFERENTIATION

INVESTIGATING NEUTROPHILIC INFLAMMATION AS AN APOE GENOTYPE-SPECIFIC MEDIATOR OF NEUROINFLAMMATION AND COGNITIVE DECLINE IN AGING - PROJECT SUMMARY THE PRESENCE OF THE 4 ALLELE OF APOE (APOE4) IS THE GREATEST GENETIC RISK FACTOR FOR LATE ONSET ALZHEIMER’S DISEASE (AD), INCREASING THE RISK APPROXIMATELY 12-FOLD WHEN HOMOZYGOUS FOR APOE4 COMPARED TO THE MOST COMMON APOE3/APOE3 GENOTYPE. HOWEVER, THE MECHANISMS BY WHICH DIFFERENT APOE ALLELES MEDIATE ALZHEIMER’S RISK ARE UNCLEAR. THE OVERALL GOALS FOR THIS STUDY ARE TO 1) INVESTIGATE NEUTROPHIL ACTIVATION AND LIFESPAN AS THERAPEUTIC TARGETS TO REDUCE AD RISK OR PROGRESSION IN THE CONTEXT OF DIFFERENT APOE GENOTYPES AND 2) IDENTIFY MICROBIAL INTERACTIONS THAT REPRESENT PROMISING TARGETS TO REDUCE NEUTROPHILIC INFLAMMATION IN THE CONTEXT OF DIFFERENT APOE GENOTYPES. A MULTITUDE OF DATA DEMONSTRATE THAT INDIVIDUALS WITH DIFFERENT APOE GENOTYPES VARY IN THEIR RESPONSES TO INFLAMMATORY STIMULI, AND APOE- MODULATED NEUROINFLAMMATION IS EMERGING AS A POTENTIAL NEW MEDIATOR OF APOE GENOTYPE-SPECIFIC COGNITIVE DECLINE. WE PROPOSE THAT THE GASTROINTESTINAL (GI) AND PERIPHERAL IMMUNE SYSTEMS REPRESENT A LIKELY BRIDGE BETWEEN INFECTION OR MICROBIAL DYSBIOSIS AND NEUROINFLAMMATION, AND THAT NEUTROPHILS, AS THE MOST ABUNDANT LEUKOCYTE WITH GREAT POTENTIAL FOR INFLAMMATORY DAMAGE, MEDIATE ALTERED RESPONSES IN INDIVIDUALS WITH DIFFERENT APOE ALLELES TO DRIVE NEUROINFLAMMATION AND COGNITIVE DECLINE. OUR HYPOTHESIS IS THAT APOE4 INCREASES NEUTROPHIL ACTIVATION AND LIFESPAN IN THE GI, PERIPHERY, AND BRAIN, THUS CONTRIBUTING TO NEUROINFLAMMATION AND COGNITIVE DECLINE. THIS HYPOTHESIS IS BASED ON COMPELLING EVIDENCE FROM PUBLISHED WORK AND OUR PRELIMINARY DATA. STUDIES HAVE DEMONSTRATED THAT NEUTROPHILS INFILTRATE THE BRAIN VASCULATURE AND PARENCHYMA DURING AD AND NEUTROPHIL ACTIVATION IN THE PERIPHERY CORRESPONDS WITH DISEASE PROGRESSION IN AD. OUR PRELIMINARY DATA SUGGESTS THAT APOE ALTERS NEUTROPHIL ACTIVATION IN A GENOTYPE- SPECIFIC MANNER, AS HAS BEEN OBSERVED PREVIOUSLY IN GLIAL CELLS. WE WILL ADDRESS OUR HYPOTHESIS AND ACHIEVE OUR STUDY GOALS BY PURSUING THE FOLLOWING THREE AIMS: 1) INVESTIGATE NEUTROPHIL LIFESPAN, ACTIVATION, AND FUNCTIONALITY IN THE GI TRACT, PERIPHERY, AND BRAIN BASED ON APOE GENOTYPE AND AGE IN MICE EXPRESSING HUMAN APOE2, APOE3, AND APOE4 UNDER THE ENDOGENOUS PROMOTOR (APOE-TR); 2) INVESTIGATE MICROBIOME CHANGES LONGITUDINALLY IN APOE-TR MICE AND APOE MODULATION OF NEUTROPHIL RESPONSES TO APOE GENOTYPE-SPECIFIC COMMENSAL BACTERIA AND A; AND 3) INVESTIGATE NEUTROPHILS AS MECHANISTIC DRIVERS OF NEUROINFLAMMATION AND COGNITIVE IMPAIRMENT IN RESPONSE TO INFLAMMATORY STIMULI IN THE CONTEXT OF DIFFERENT APOE GENOTYPES. THIS PROJECT IS SIGNIFICANT BECAUSE NO STUDIES HAVE INVESTIGATED APOE-SPECIFIC NEUTROPHIL RESPONSES DESPITE A PROPOSED ROLE FOR NEUTROPHILS IN AD. THIS PROJECT IS TRANSLATIONALLY INNOVATIVE AND ACTIONABLE BECAUSE THE INFORMATION GAINED WILL INFORM THE TESTING OF NEUTROPHIL-TARGETED OR MICROBIAL-TARGETED THERAPEUTIC APPROACHES IN AD MOUSE MODELS AND HUMANS AND DETERMINE IF THEY SHOULD BE TAILORED BASED ON APOE GENOTYPE.

CNS STEM CELLS FOR NEURODEGENERATIVE DISEASE RESEARCH

INVESTIGATING NEUTROPHILIC INFLAMMATION AS AN APOE GENOTYPE-SPECIFIC MEDIATOR OF COGNITIVE DECLINE AND REDUCED SYNAPTIC PLASTICITY IN AGING - PROJECT SUMMARY THE PRESENCE OF THE EPSILON4 ALLELE OF APOE (APOE4) IS THE GREATEST GENETIC RISK FACTOR FOR LATE ONSET ALZHEIMER’S DISEASE, INCREASING THE RISK APPROXIMATELY 12-FOLD WHEN HOMOZYGOUS FOR APOE4 COMPARED TO THE MOST COMMON APOE3/APOE3 GENOTYPE. HOWEVER, THE MECHANISMS BY WHICH DIFFERENT APOE ALLELES MEDIATE ALZHEIMER’S RISK IS UNCLEAR. THE OVERALL GOALS FOR THIS STUDY ARE TO 1) INVESTIGATE NEUTROPHIL ACTIVATION AND LIFESPAN AS THERAPEUTIC TARGETS TO REDUCE ALZHEIMER’S DISEASE RISK OR PROGRESSION IN THE CONTEXT OF DIFFERENT APOE GENOTYPES AND 2) IDENTIFY MICROBIAL INTERACTIONS THAT REPRESENT PROMISING TARGETS TO REDUCE NEUTROPHILIC INFLAMMATION IN THE CONTEXT OF DIFFERENT APOE GENOTYPES. A MULTITUDE OF DATA DEMONSTRATE THAT INDIVIDUALS WITH DIFFERENT APOE GENOTYPES VARY IN THEIR RESPONSES TO INFLAMMATORY STIMULI, AND APOE- MODULATED NEUROINFLAMMATION IS EMERGING AS A POTENTIAL NEW MEDIATOR OF APOE-SPECIFIC COGNITIVE DECLINE. WE PROPOSE THAT THE GASTROINTESTINAL AND PERIPHERAL IMMUNE SYSTEMS REPRESENT A LIKELY BRIDGE BETWEEN INFECTION OR MICROBIAL DYSBIOSIS AND NEUROINFLAMMATION, AND THAT NEUTROPHILS, AS THE MOST ABUNDANT LEUKOCYTE WITH GREAT POTENTIAL FOR INFLAMMATORY DAMAGE, MEDIATE ALTERED RESPONSES IN INDIVIDUALS WITH DIFFERENT APOE ALLELES TO DRIVE COGNITIVE DECLINE. OUR HYPOTHESIS IS THAT APOE4 INCREASES NEUTROPHIL ACTIVATION AND LIFESPAN IN THE GI, PERIPHERY, AND BRAIN, THUS CONTRIBUTING TO COGNITIVE DECLINE AND REDUCED SYNAPTIC PLASTICITY IN INDIVIDUALS WITH THE APOE4 ALLELE. THIS HYPOTHESIS IS BASED ON COMPELLING EVIDENCE FROM PUBLISHED WORK AND OUR PRELIMINARY DATA. STUDIES HAVE DEMONSTRATED THAT NEUTROPHILS INFILTRATE THE BRAIN VASCULATURE AND PARENCHYMA DURING AD AND NEUTROPHIL ACTIVATION IN THE PERIPHERY CORRESPONDS WITH DISEASE PROGRESSION IN AD. OUR PRELIMINARY DATA SUGGESTS THAT APOE ALTERS NEUTROPHIL ACTIVATION TO INFLAMMATORY STIMULI IN AN ISOTYPE-SPECIFIC MANNER, AS HAS BEEN OBSERVED PREVIOUSLY IN GLIAL CELLS. WE WILL ADDRESS OUR HYPOTHESIS AND ACHIEVE OUR STUDY GOALS BY PURSUING THE FOLLOWING THREE AIMS: 1) EXAMINE NEUTROPHIL ACTIVATION, LIFESPAN, AND FUNCTION IN THE GI TRACT, PERIPHERY, AND BRAIN THROUGHOUT THE LIFESPAN IN MICE EXPRESSING HUMAN APOE2, APOE3, AND APOE4 UNDER THE ENDOGENOUS PROMOTOR (APOE-TR); 2) INVESTIGATE ROLES OF THE MICROBIOME AND BACTERIA-NEUTROPHIL INTERACTIONS IN APOE-SPECIFIC NEUTROPHIL ALTERATIONS, AND 3) DETERMINE IF NEUTROPHILS MEDIATE NEUROINFLAMMATION AND COGNITIVE DECLINE IN AN APOE- SPECIFIC MANNER IN RESPONSE TO LOW LEVEL INFLAMMATORY STIMULI VIA NEUTROPHIL DEPLETION STUDIES. THIS PROJECT IS SIGNIFICANT BECAUSE NO STUDIES HAVE INVESTIGATED APOE-SPECIFIC NEUTROPHIL RESPONSES DESPITE A PROPOSED ROLE FOR NEUTROPHILS IN ALZHEIMER’S DISEASE. THIS PROJECT IS TRANSLATIONALLY INNOVATIVE AND ACTIONABLE BECAUSE THE INFORMATION GAINED WILL INFORM THE TESTING OF NEUTROPHIL-TARGETED OR MICROBIAL-TARGETED THERAPEUTIC APPROACHES IN ALZHEIMER’S DISEASE MOUSE MODELS AND HUMANS AND DETERMINE IF THEY SHOULD BE TAILORED BASED ON APOE GENOTYPE.

THE ROLE OF RPE-DERIVED EXOSOMES IN DEPOSIT FORMATION AND ECM MODULATION - ABSTRACT THE RETINAL PIGMENTED EPITHELIUM (RPE) FUNCTIONS TO MAINTAIN THE OUTER BLOOD-RETINAL BARRIER AND TO SUPPORT PHO- TORECEPTOR FUNCTION, INCLUDING REGENERATION OF VISUAL PIGMENT AND TURNOVER OF OUTER SEGMENTS. DYSFUNCTION OF THE RPE UNDERLIES PATHOLOGY LEADING TO DEVELOPMENT OF AGE-RELATED MACULAR DEGENERATION (AMD), THE LEADING CAUSE OF VISION LOSS AMONG OLDER AMERICANS. GIVEN THAT A MAJOR FUNCTION OF THE RPE IS TO PROCESS PHOTORECEP- TOR OUTER SEGMENTS, THE PROPER FUNCTIONING OF THE RPE ENDOSOMAL PATHWAY IS IMPORTANT FOR RETINAL HEALTH. MULTI- PLE LINES OF EVIDENCE INDICATE THAT ONE OF THE MAJOR CULPRITS OBSERVED IN RPE DYSFUNCTION IS DYSREGULATION IN THE ENDOSOMAL PATHWAY. IT IS THOUGHT THAT IN AMD THIS DYSREGULATION IN RPE CELLS IS AT LEAST IN PART RESPONSIBLE FOR THE FORMATION OF DRUSEN (PROTEIN- AND LIPID-RICH EXTRACELLULAR DEPOSITS) BETWEEN THE BASAL LAMINA OF THE RPE AND THE PENTALAMINAR COLLAGEN- AND ELASTIN-RICH BRUCH’S MEMBRANE (BRM). AT PRESENT, THE EXACT MECHANISMS FOR DRUSEN FORMATION ARE UNKNOWN. SINCE RPE-RELEASED EXOSOMES AND OTHER EXTRACELLULAR VESICLES (EVS) ARE ESSENTIAL PARTS OF THE ENDOSOMAL PATHWAY, WE HYPOTHESIZE THAT EXOSOMES RELEASED FROM STRESSED RPE CELLS ARE DISTINCT FROM THOSE RELEASED FROM UNSTRESSED RPE CELLS, AND THAT THESE EXOSOMES ARE INVOLVED IN THE PATHOGNOMONIC DEPOSIT FORMATION AND ECM CHANGES THAT UNDERLIE THE EARLY AND LATE STAGES OF AMD. ACCORDINGLY, APPROACHES TO CHARACTERIZE THESE VESICLES AND MODULATE THEIR RELEASE HAVE HIGH POTENTIAL TO GIVE IMPORTANT INSIGHT TO DISEASE MECHANISMS AND NEW TREATMENT TARGETS. SIGNIFICANTLY, VERY LITTLE IS KNOWN ABOUT RPE-RELEASED EXOSOMES AND OTHER EVS. BY EVALUATING TWO COMPLEMENTARY IN VITRO AND EX VIVO AMD MODELS, OUR OVERALL GOAL FOR THIS PROJECT IS TO DETERMINE THE ROLE OF EXOSOME SECRETION IN SUB-RPE DEPOSIT FOR- MATION AND IN ECM CHANGES UNDER CONDITIONS RELEVANT TO AMD, AND WHETHER PHARMACOLOGICAL OR GENE THERAPY/BIOLOGICAL THERAPEUTIC INTERVENTIONS ARE POSSIBLE. IN THE FIRST AIM, WE WILL CHARACTERIZE AND QUANTIFY THE PROTEIN AND LIPID COMPOSITION OF SUB-RPE DEPOSITS, ECM AND BASAL-SIDE EXOSOMES IN RPE STRESSED BY PATHO- PHYSIOLOGICAL CONDITIONS IMPLICATED IN AMD (OXIDATIVE STRESS, COMPLEMENT DYSREGULATION, AND AGE), WHILE MODULATING EXOSOME RELEASE BY BOTH PHARMACOLOGICAL AND GENETIC APPROACHES. IN THE SECOND AIM WE WILL CHARACTERIZE THE PROTEIN AND LIPID CONTENT IN DRUSEN AND BRM FROM HUMAN POST-MORTEM EYES FROM NORMAL AGED AND AMD DONORS, BY EXHAUSTIVE PROTEOMIC AND LIPIDOMIC ANALYSES WITH CUTTING-EDGE INSTRUMENTATION AND ANALYSIS METHODOLOGIES. THIS WORK SERVES AS A PRECLINICAL STUDY AND PROOF OF PRINCIPLE TO PROBE THE POTENTIAL OF MODULATING EXOSOME SECRETION AND TARGET EXOSOME COMPOSITION AS A THERAPEUTIC APPROACH FOR TREATING AMD.

PARKIN AND MGRN1: COMMON ROLES IN MITOCHONDRIA AND NEURODEGENERATION?

OLYMPUS FV1000 INVERTED SPECTRAL CONFOCAL SYSTEM

A MULTI-OMIC AND INTEGRATIVE LONGITUDINAL EVALUATION OF THE ROLE OF LIPID, ANTIOXIDANT, AND OSMOPROTECTANT METABOLITES IN THE GENITOURINARY SYNDROME OF MENOPAUSE BY RACE AND ETHNICITY. - THE GENITOURINARY SYNDROME OF MENOPAUSE (GSM) IS AN AGE-RELATED CHRONIC, PROGRESSIVE UROGENITAL CONDITION THAT DISPROPORTIONATELY AFFECTS POSTMENOPAUSAL WOMEN AND CONTRIBUTES >$3 BILLION ANNUALLY TO US HEALTHCARE COSTS. THE IMPACT OF GSM IS EXTENSIVE AND AFFECTS >62 MILLION US WOMEN. RACIAL AND ETHNIC MINORITIES ARE DISPROPORTIONATELY AFFECTED BUT REMAIN UNDERREPRESENTED IN AGING AND SEXUAL HEALTH RELATED STUDIES. THE VAGINAL MICROBIOTA IS A CRITICAL DETERMINANT IN UROGENITAL AND SEXUAL HEALTH, AND WE HYPOTHESIZE THIS RELATIONSHIP MAY BE MEDIATED THROUGH HOST-MICROBIAL METABOLITE INTERACTIONS. AS WOMEN AGE, ESTROGEN LEVELS DECLINE DISRUPTING ESTROGEN-DEPENDENT PROCESSES. IN A LARGE COHORT (N=1190), I OBSERVED CHRONOLOGICAL AGING TO BE ASSOCIATED WITH ALTERED LIPID METABOLISM (E.G., LIPID PEROXIDATION), LOSS OF PROTECTIVE VAGINAL LACTOBACILLI, CELLULAR DAMAGE (E.G., INCREASED OXIDATIVE STRESS METABOLITES), AND A DECLINE IN VAGINAL ANTIOXIDANTS (E.G., VITAMINS). OXIDATIVE STRESS INDUCES INFLAMMATION, AND BIOMARKERS OF OXIDATIVE STRESS WITHIN SERUM AND PLASMA HAVE BEEN LINKED TO AGE- RELATED PATHOLOGIES (E.G., OSTEOPOROSIS, CARDIOVASCULAR DISEASE, AND ALZHEIMER’S DISEASE). SOME ANTIOXIDANTS CAN BE PRODUCED BY THE HOST (E.G., GLUTATHIONE), WHILE OTHERS MUST BE OBTAINED THROUGH THE DIET AND MICROBIOTA (E.G., VITAMINS). ANTIOXIDANTS SERVE TO NEUTRALIZE OXIDATIVE AND OSMOTIC STRESS AND THEIR DECLINE INCREASES SUSCEPTIBILITY TO OXIDATIVE STRESS RELATED PATHOLOGIES. THIS HAS NOT BEEN YET DESCRIBED WITHIN THE VAGINA. THE K99 PHASE PROPOSES TO (1) CHARACTERIZE THE RELATION OF VAGINAL LAO PROFILES WITH REPRODUCTIVE STAGE, CHRONOLOGICAL AGE, AND RACE/ETHNICITY; AND (2) QUANTIFY THE LONGITUDINAL MEDIATION BETWEEN LAO PROFILES AND GSM BY COMBINING MACHINE LEARNING, STRUCTURAL MODELS, AND MULTI-OMICS (METABOLOMICS, IMMUNOLOGY, AND MICROBIOTA) VAGINAL SAMPLES LEVERAGED FOR THIS PROPOSAL ARE AVAILABLE VIA AN NIA AWARD (R01AG069915, PI: SHARDELL, CO-SPONSOR) AND REPRESENT A LONGITUDINAL COHORT (N=500 PARTICIPANTS; 25% RACIAL/ETHNIC MINORITIES; 1200 SAMPLES) WITH VARYING SIGNS AND SYMPTOMS OF GSM. THIS WILL BE THE LARGEST VAGINAL METABOLOMIC COHORT EMPHASIZING POST-MENOPAUSAL WOMEN, TO DATE. SAMPLES HAVE ALREADY BEEN SENT FOR MICROBIOME, METABOLOMIC, AND CYTOKINE PROFILING. I WILL COMPLETE FORMAL COURSEWORK AND MENTORING IN IMMUNOLOGY, MACHINE LEARNING, AND STRUCTURAL MODELS IN PREPARATION FOR THE INDEPENDENT R00 PHASE WHERE I PROPOSE TO DETERMINE THE INFLAMMATORY RESPONSE OF HUMAN VAGINAL EPITHELIAL CELLS [HVECS] FOLLOWING EXPOSURE TO LAO METABOLITES AND MICROBIOTA. INFORMATION GLEANED DURING THIS WORK WILL BE USEFUL IN DEVELOPING TARGETED INTERVENTIONS (E.G., ANTIOXIDANT THERAPY) FOR GSM AND WILL INFORM AN R01 APPLICATION FOR A LARGE-SCALE, MULTI-CENTER VALIDATION STUDY THAT WILL PERMIT TARGETED MANAGEMENT OF GSM. ALL AIMS WILL CONTRIBUTE TO MY LONG-TERM GOAL OF BECOMING AN INDEPENDENT INVESTIGATOR IN MICROBIOLOGY WITH A FOCUS ON IMPROVING GYNECOLOGICAL OUTCOMES AND ADVOCATING ACCESSIBILITY (LOWER COST, PERSONALIZED TARGETS OF INTERVENTION) FOR COMMUNITIES THAT HAVE BEEN HISTORICALLY UNDERSERVED AND MARGINALIZED. MY HERITAGE WILL DIRECT THE FOCI OF THIS PROPOSAL AND ALIGNS WITH MOSAIC K99/R00 OBJECTIVES.

ENHANCING IMAGING EFFICIENCY THROUGH AUTOMATED SLIDE SCANNING IMAGE ACQUISITION - TITLE: ENHANCING IMAGING EFFICIENCY THROUGH AUTOMATED SLIDE SCANNING IMAGE ACQUISITION ABSTRACT: THE MCLAUGHLIN RESEARCH INSTITUTE IS REQUESTING FUNDS TO PURCHASE AN APEXVIEW APX100 BENCHTOP FLUORESCENCE MICROSCOPE AND SLIDE SCANNER AS AN INTEGRAL CORE COMPONENT OF OUR IMAGING SUITE. THE INSTITUTE’S MISSION TO SUPPORT RESEARCHERS IN ADDRESSING COMPLEX SCIENTIFIC PROBLEMS IN RURAL, AGING COMMUNITIES IS BUILT ON A LEGACY OF INNOVATIVE BIOMEDICAL RESEARCH. AS THE CLOSEST BIOMEDICAL RESEARCH INSTITUTION TO MORE THAN TWO THIRDS OF THE RESIDENTS OF MONTANA, WE SEEK TO BRING SCIENCE OPPORTUNITIES AND DISCOVERIES TO COMMUNITIES ACROSS THE STATE WHILE DOING GROUNDBREAKING SCIENCE. WHILE THE INSTITUTE HAS INVESTED IN HIGH RESOLUTION CONFOCAL MICROSCOPY SYSTEMS, THESE SYSTEMS ARE OLDER, AND SIGNIFICANT ADVANCES HAVE BEEN MADE IN THE OPTICS AND AUTOMATION SYSTEMS AVAILABLE. THE EXISTING MICROSCOPES LACK CRITICAL FEATURES AVAILABLE IN THE NEW APX100 SYSTEM. TO ADDRESS THE LACK OF CRITICAL FEATURES, WE PROPOSE FUNDS TO PURCHASE A SYSTEM THAT INCORPORATES AN AUTOMATED FULL SLIDE WORKFLOW, ADVANCED DECONVOLUTION ALGORITHMS, ENHANCED Z-STACK ACQUISITION PARAMETERS AND LARGE AREA TISSUE SCANNING FEATURES. THE CURRENT ACQUISITION PROCESSES CREATE BOTTLENECKS FOR THE DIVERSE NIH-FUNDED PROJECTS AT THE INSTITUTE. THE ADDITION OF THIS INSTRUMENT WOULD EXPEDITE RESEARCH PROGRESS THROUGH REDUCED ACQUISITION AND PROCESSING TIME IN BOTH ESTABLISHED NIH FUNDED PROJECTS AS WELL AS NEW EARLY-STAGE PILOT PROJECTS FROM A RECENT PARTNERSHIP WITH THE FIRST MEDICAL SCHOOL IN THE STATE. AS THE CLOSEST BIOMEDICAL RESEARCH INSTITUTION, GEOGRAPHICALLY, TO MOST OF THE STATE, THIS RESOURCE WOULD FILL A TECHNOLOGICAL VOID, SUBSTANTIALLY ACCELERATING THE PROGRESS OF NIH FUNDED PROJECTS. IN SUMMARY, THE APX100 WILL STIMULATE EFFECTIVE AND EFFICIENT IMAGING WORKFLOWS ENABLING ADVANCEMENT OF NIH-FUNDED PROJECTS AT THE MCLAUGHLIN RESEARCH INSTITUTE SUPPORTING SCIENTIFIC DISCOVERY IN THE UNDERSTANDING OF DISEASES AFFECTING RURAL AND AGING POPULATIONS.

MYOSIN-VA AND AXONAL PROTEIN SYNTHESIS

GE TYPHOON 9410 VARIABLE MODE IMAGER

NOVEL STEM CELL AND MOUSE MODELS TO STUDY FRONTOTEMPORAL DEMENTIA